Population Pharmacokinetic Model for Ertugliflozin in Healthy Subjects and Patients With Type 2 Diabetes Mellitus.
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ABSTRACT:
SUBMITTER: Fediuk DJ
PROVIDER: S-EPMC8359437 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and objectivesDorzagliatin is a first-in-class small molecule glucokinase activator (GKA) that improves pancreatic insulin secretion behavior and regulates hepatic glucose conversion in a glucose concentration-dependent manner. The primary objective of this study was to develop a population pharmacokinetic model of dorzagliatin to evaluate the influence of covariates, such as demographic characteristics and liver and kidney function, on the pharmacokinetics of dorzagliatin and provide a basis for medication guidance.MethodThe pharmacokinetic data of dorzagliatin in this study came from six clinical trials. Based on the combined data, a population pharmacokinetic model of dorzagliatin was established using NONMEM software (ICON, MD, USA, version 7.4.3). The algorithm used was first-order conditional estimation with interaction (FOCEI). The dorzagliatin population pharmacokinetic modeling analysis included 1062 subjects and 7686 observable concentrations. Covariates, including age (AGE), sex (GEND), body weight (TBW), body mass index (BMI), body surface area (BSA), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (CR), creatinine clearance (CRCL), and total bilirubin (TBIL), were screened using the forward-backward method. Model evaluation was performed using goodness-of-fit plots, prediction corrected visual prediction check (pcVPC), and bootstrap.ResultsConcentration data of dorzagliatin in the dose range were best characterized by a two-compartment model with sequential zero-order then first-order absorption and first-order elimination. The final model estimated dorzagliatin data for typical male subjects (69 kg body weight, 18 U/L AST and 55 years old); the apparent total clearance (CL/F) was 10.4 L/h, apparent volume of central compartment distribution (Vc/F) was 80.6 L, inter-compartmental clearance (Q/F) was 3.02 L/h, apparent volume of peripheral compartment distribution (Vp/F) was 26.5 L, absorption rate constant (Ka) was 3.29 h-1, and duration of zero-order absorption (D1) was 0.418 h. The inter-individual variation of CL/F, Vc/F, Vp/F, and D1 was 22.5%, 14.9%, 48.8%, and 82.8%, respectively.ConclusionThe two-compartment linear pharmacokinetic model with zero- and first-order sequential absorption adequately described the pharmacokinetic characteristics of dorzagliatin. Body weight, aspartate aminotransferase, and age had a statistically significant effect on the CL/F of dorzagliatin. Body weight and sex had a statistically significant effect on Vc/F. However, considering the clinically insignificant changes in the magnitude of steady-state exposure caused by these covariates, as well as the minimal changes in the steady-state exposure for individuals with mild and moderate impaired hepatic function and all stages of renal impairment, dose adjustments based on the tested covariates or for specific populations are deemed unnecessary.
| S-EPMC10520121 | biostudies-literature
Project description:More than 422 million people worldwide have diabetes, with 90-95% having type 2 diabetes (T2D). Glycemic control of T2D has demonstrated reductions in microvascular complications but recent data have demonstrated improvements in macrovascular outcomes with sodium-glucose cotransporter 2 (SGLT2) inhibitors. Ertugliflozin is the most recent SGLT2 inhibitor approved in the USA and Europe for the treatment of T2D. This narrative review aims to present and discuss the efficacy, safety, cardiovascular (CV), and renal outcomes related to the use of ertugliflozin in T2D. Ertugliflozin has been evaluated in eight clinical trials (n=5248) with a focus on glycemic control. These trials have demonstrated improvement in glycosylated hemoglobin (0.6-1%), fasting plasma glucose (30-50 mg/dL), 2-hour postprandial glucose (60-70 mg/dL), decreased body weight (2-3 kg), and lowering of blood pressure (3-5 mmHg) in patients with T2D when ertugliflozin is used as monotherapy or in addition to metformin, sitagliptin, insulin, and/or sulfonylureas. The findings from the VERTIS-CV trial (n=8246) were recently published and demonstrated that ertugliflozin use in patients with T2D and atherosclerotic CV disease is safe but did not demonstrate superiority in the lowering of major CV events compared to placebo. Other SGLT2 inhibitors, such as empagliflozin and canagliflozin, have demonstrated this benefit. The VERTIS-CV trial demonstrated that the use of ertugliflozin led to a decrease in the number of hospitalizations for heart failure and this lends further support that this benefit is a class effect of SGLT2 inhibitors.
| S-EPMC7707814 | biostudies-literature
Project description:Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven-compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent.
| S-EPMC4120995 | biostudies-literature
Project description:Ertugliflozin is a highly selective and potent inhibitor of the sodium-glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. The glycemic efficacy of sodium-glucose cotransporter 2 inhibitors such as ertugliflozin depends on glucose filtration through the kidney. This phase 1, open-label study evaluated the effect of renal impairment on the pharmacokinetics, pharmacodynamics, and tolerability of ertugliflozin (15 mg) in type 2 diabetes mellitus and healthy subjects with normal renal function (estimated glomerular filtration rate not normalized for body surface area ?90 mL/min) and type 2 diabetes mellitus subjects with mild (60-89 mL/min), moderate (30-59 mL/min), or severe (<30 mL/min) renal impairment (n = 36). Blood and urine samples were collected predose and over 96 hours postdose for pharmacokinetic evaluation and measurement of urinary glucose excretion over 24 hours. Log-linear regression analyses indicated predicted mean area under the concentration-time curve values for mild, moderate, and severe renal function groups that were ?70% higher relative to subjects with normal renal function. Generally consistent results were obtained with categorical analysis based on analysis of variance. The increase in ertugliflozin exposure in subjects with renal impairment is not expected to be clinically meaningful. Regression analysis of change from baseline in urinary glucose excretion over 24 hours vs estimated glomerular filtration rate showed a decrease in urinary glucose excretion with declining renal function. A single 15-mg dose of ertugliflozin was well tolerated in all groups.
| S-EPMC5655776 | biostudies-literature
Project description:AimPost-hoc analysis of the efficacy and safety of ertugliflozin in East/Southeast (E/SE) Asian patients with type 2 diabetes mellitus (T2DM).Materials and methodsEfficacy evaluations used data from randomized, double-blind, phase 3 studies: a pool of two 26-week placebo-controlled studies and one 52-week active-comparator (glimepiride) study. Least squares mean change from baseline was calculated for HbA1c, fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events based on pooled data (broad pool) from seven phase 3 studies (including studies in the efficacy analysis).ResultsAmong 161 E/SE Asian patients in the placebo pool (ertugliflozin, n = 106), ertugliflozin reduced HbA1c, FPG, BW and SBP from baseline at week 26. The placebo-adjusted changes from baseline for ertugliflozin 5 and 15 mg were: HbA1c, -0.9% and -1.0%; BW, -2.1 and -1.9 kg; and SBP, -3.3 and -3.5 mmHg, respectively. Among 174 E/SE Asian patients in the active-comparator study (ertugliflozin, n = 118), HbA1c changes from baseline at week 52 were -0.6%, -0.6% and -0.7% for ertugliflozin 5 mg, 15 mg and glimepiride, respectively. Ertugliflozin 5 and 15 mg reduced BW from baseline by -4.3 and -4.1 kg, respectively, and SBP by -7.4 and -9.3 mmHg, respectively, compared with glimepiride. Safety findings were generally consistent with overall ertugliflozin safety data published to date.ConclusionsTreatment with ertugliflozin was associated with reductions in HbA1c, FPG, BW and SBP, and was generally well tolerated in E/SE Asian patients with T2DM. ClinicalTrials.gov identifier: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, NCT02226003.
| S-EPMC7078752 | biostudies-literature
Project description:AimsLenvatinib was recently approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Here, we characterized the pharmacokinetic (PK) profile of lenvatinib and identified intrinsic and extrinsic factors that explain interindividual PK variability in humans.MethodsThis population PK analysis used pooled data from 15 clinical studies, including eight phase 1 studies in healthy subjects, four phase 1 studies in patients with solid tumours, two phase 2 studies in patients with thyroid cancer and one phase 3 study in patients with RR-DTC.ResultsThe final pooled dataset included data from 779 subjects receiving 3.2-32 mg oral lenvatinib, mainly once daily as tablets or capsules. Lenvatinib PK was best described by a three-compartment model with linear elimination. Lenvatinib absorption was best described by simultaneous first- and zero-order absorption. The population mean value for lenvatinib apparent clearance (CL/F) was 6.56 l h(-1) [percent coefficient of variation (%CV) 25.5], and was independent of dose and time. The relative bioavailability of lenvatinib in capsule form was 90% vs. tablets (%CV 30.2). The final PK model included significant but marginal effects of body weight (2.8% of CL/F variation), liver-function markers [alkaline phosphatase (-11.7%) and albumin (-6.3%)] and concomitant cytochrome P450 3A4 inducers (+30%) and inhibitors (-7.8%) on lenvatinib CL/F. Lenvatinib PK was unaffected by pH-elevating agents, dose, age, sex, race, alanine aminotransferase, aspartate aminotransferase or bilirubin levels, or renal function.ConclusionsThe significant effects of several covariates on lenvatinib PK variability were small in magnitude, and therefore were not considered clinically relevant, or to warrant any dose adjustment.
| S-EPMC4876185 | biostudies-literature
Project description:The pharmacokinetic properties of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus (T2D), have been established in healthy individuals and subjects with T2D. Liraglutide has been under investigation as adjunct treatment to insulin in type 1 diabetes mellitus (T1D). This single-center, double-blind, placebo-controlled, crossover, clinical pharmacology trial is the first to analyze the pharmacokinetic properties of liraglutide as add-on to insulin in T1D.Subjects (18-64 years; body mass index 20.0-28.0 kg/m2; glycated hemoglobin ?9.5 %) were randomized 1:1:1 to 0.6, 1.2, or 1.8 mg liraglutide/placebo. Each group underwent two 4-week treatment periods (liraglutide then placebo or placebo then liraglutide) separated by a 2- to 3-week washout. Both trial drugs were administered subcutaneously, once daily, as adjunct to insulin. A stepwise hypoglycemic clamp was performed at the end of each treatment period (data reported previously). Pharmacokinetic endpoints were derived from liraglutide concentration-time curves after the final dose and exposure was compared with data from previous trials in healthy volunteers and subjects with T2D.The pharmacokinetic properties of liraglutide in T1D were comparable with those observed in healthy volunteers and subjects with T2D. Area under the steady-state concentration-time curve (AUC) and maximum plasma concentration data were consistent with dose proportionality of liraglutide. Comparison of dose-normalized liraglutide AUC suggested that exposure in T1D, when administered with insulin, is comparable with that observed in T2D.Liraglutide, administered as adjunct to insulin in subjects with T1D, shows comparable pharmacokinetics to those in subjects with T2D. ClinicalTrials.gov Identifier: NCT01536665.
| S-EPMC5069309 | biostudies-literature
Project description:OBJECTIVE:This study aimed to evaluate ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus. METHODS:Data from three placebo-controlled, randomized, Phase 3 studies were pooled. Patients with baseline BMI ≥ 25 (1,377/1,544; 89%) were assessed with a stratification by BMI subgroup. RESULTS:At week 26, reductions from baseline in glycated hemoglobin A1c (HbA1c), fasting plasma glucose, body weight (BW), and systolic blood pressure (SBP) were greater with ertugliflozin versus placebo. For placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively, least squares mean change was 0.1%, -0.8%, and -0.9% for HbA1c and -1.2 kg, -3.1 kg, and -3.2 kg for BW. HbA1c reductions were consistent across BMI subgroups. For ertugliflozin 5 mg and 15 mg, least squares mean change (placebo adjusted) in absolute BW was -1.4 kg and -1.2 kg for BMI 25 to < 30, -1.8 kg and -1.9 kg for BMI 30 to < 35, and -2.5 kg and -2.9 kg for BMI ≥ 35. Percent BW changes were similar across BMI subgroups. Incidence of adverse events was 52.5%, 44.6%, and 50.1% with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. CONCLUSIONS:Meaningful reductions in HbA1c, fasting plasma glucose, BW, and SBP were observed with ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus. Ertugliflozin improved HbA1c and SBP and reduced BW across BMI subgroups. Ertugliflozin was generally well tolerated.
| S-EPMC7217180 | biostudies-literature
Project description:The purpose of this study was to perform population pharmacokinetic (PPK) analysis of tiropramide in healthy Korean subjects, as well as to investigate the possible effects of various covariates on pharmacokinetic (PK) parameters of tiropramide. Although tiropramide is commonly used in digestive system-related diseases as an antispasmodic, PPK reporting and factors affecting PKs are not clearly reported. Thus, this study for healthy subjects is very significant because it could find new covariates in patients that had not been reported before or predict PPK for patients in the clinic by establishing PPK in healthy adults. By using Phoenix NLME, PK, demographic, and genetic data (collected to explain PK diversity of tiropramide in population) analyses were performed. As a basic model, a one-compartment with first-order absorption and lag-time was established and extended to include covariates that influenced the inter-subject variability. The total protein significantly influenced the distribution volume and systemic clearance of tiropramide, but genetic factors such as ABCB1 (1236C>T, 2677G>T/A, and 3435C>T), CYP2D6 (*1 and *10), OCT2 (808G>T), and PEPT1 (1287G>C) genes did not show any significant association with PK parameters of tiropramide. The final PPK model of tiropramide was validated, and suggested that some of the PK diversity in the population could be explained. Herein, we first describe the establishment of the PPK model of tiropramide for healthy Korean subjects, which may be useful as a dosing algorithm for the diseased population.
| S-EPMC7238185 | biostudies-literature
Project description:The aims of this study were: (1) to perform population pharmacokinetic analysis of cefaclor in healthy Korean subjects, and (2) to investigate possible effects of various covariates on pharmacokinetic parameters of cefaclor. Although cefaclor belongs to the cephalosporin family antibiotic that has been used in various indications, there have been very few population studies on factors affecting its pharmacokinetics. Therefore, this study is very important in that effective therapy could be possible through a population pharmacokinetic study that explores effective covariates related to cefaclor pharmacokinetic diversity between individuals. Pharmacokinetic results of 48 subjects with physical and biochemical parameters were used for the population pharmacokinetic analysis of cefaclor. A one-compartment with lag-time and first-order absorption/elimination was constructed as a base model and extended to include covariates that could influence between-subject variability. Creatinine clearance and body weight significantly influenced systemic clearance and distribution volume of cefaclor. Cefaclor's final population pharmacokinetic model was validated and some of the population's pharmacokinetic diversity could be explained. Herein, we first describe the establishment of a population pharmacokinetic model of cefaclor for healthy Koreans that might be useful for customizing cefaclor or exploring additional covariates in patients.
| S-EPMC8160640 | biostudies-literature